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Activity-Regulated Cytoskeleton-Associated Protein Accumulates in the Nucleus in Response to Cocaine and Acts as a Brake on Chromatin Remodeling and Long-Term Behavioral Alterations.
Salery, Marine; Dos Santos, Marc; Saint-Jour, Estefani; Moumné, Lara; Pagès, Christiane; Kappès, Vincent; Parnaudeau, Sébastien; Caboche, Jocelyne; Vanhoutte, Peter.
Afiliação
  • Salery M; INSERM, UMR-S 1130, Neuroscience Paris Seine, Institute of Biology Paris Seine; Paris, France; Sorbonne Universités, UPMC Université Paris 06, UM CR18, Neuroscience Paris Seine, Paris, France.
  • Dos Santos M; INSERM, UMR-S 1130, Neuroscience Paris Seine, Institute of Biology Paris Seine; Paris, France; Sorbonne Universités, UPMC Université Paris 06, UM CR18, Neuroscience Paris Seine, Paris, France.
  • Saint-Jour E; INSERM, UMR-S 1130, Neuroscience Paris Seine, Institute of Biology Paris Seine; Paris, France; Sorbonne Universités, UPMC Université Paris 06, UM CR18, Neuroscience Paris Seine, Paris, France.
  • Moumné L; INSERM, UMR-S 1130, Neuroscience Paris Seine, Institute of Biology Paris Seine; Paris, France; Sorbonne Universités, UPMC Université Paris 06, UM CR18, Neuroscience Paris Seine, Paris, France.
  • Pagès C; INSERM, UMR-S 1130, Neuroscience Paris Seine, Institute of Biology Paris Seine; Paris, France; Sorbonne Universités, UPMC Université Paris 06, UM CR18, Neuroscience Paris Seine, Paris, France.
  • Kappès V; INSERM, UMR-S 1130, Neuroscience Paris Seine, Institute of Biology Paris Seine; Paris, France; Sorbonne Universités, UPMC Université Paris 06, UM CR18, Neuroscience Paris Seine, Paris, France.
  • Parnaudeau S; INSERM, UMR-S 1130, Neuroscience Paris Seine, Institute of Biology Paris Seine; Paris, France; Sorbonne Universités, UPMC Université Paris 06, UM CR18, Neuroscience Paris Seine, Paris, France.
  • Caboche J; INSERM, UMR-S 1130, Neuroscience Paris Seine, Institute of Biology Paris Seine; Paris, France; Sorbonne Universités, UPMC Université Paris 06, UM CR18, Neuroscience Paris Seine, Paris, France.
  • Vanhoutte P; INSERM, UMR-S 1130, Neuroscience Paris Seine, Institute of Biology Paris Seine; Paris, France; Sorbonne Universités, UPMC Université Paris 06, UM CR18, Neuroscience Paris Seine, Paris, France. Electronic address: peter.vanhoutte@upmc.fr.
Biol Psychiatry ; 81(7): 573-584, 2017 04 01.
Article em En | MEDLINE | ID: mdl-27567310
ABSTRACT

BACKGROUND:

Addiction relies on persistent alterations of neuronal properties, which depends on gene regulation. Activity-regulated cytoskeleton-associated protein (Arc) is an immediate early gene that modulates neuronal plasticity underlying learning and memory. Its role in cocaine-induced neuronal and behavioral adaptations remains elusive.

METHODS:

Acute cocaine-treated mice were used for quantitative reverse-transcriptase polymerase chain reaction, immunocytochemistry, and confocal imaging from striatum. Live imaging and transfection assays for Arc overexpression were performed from primary cultures. Molecular and behavioral adaptations to cocaine were studied from Arc-deficient mice and their wild-type littermates.

RESULTS:

Arc messenger RNA and proteins are rapidly induced in the striatum after acute cocaine administration, via an extracellular-signal regulated kinase-dependent de novo protein synthesis. Although detected in dendrites, Arc accumulates in the nucleus in active zones of transcription, where it colocalizes with phospho-Ser10-histone H3, an important component of nucleosomal response. In vitro, Arc overexpression downregulates phospho-Ser10-histone H3 without modifying extracellular-signal regulated kinase phosphorylation in the nucleus. In vivo, Arc-deficient mice display decreased heterochromatin domains, a high RNA-polymerase II activity and enhanced c-Fos expression. These mice presented an exacerbated psychomotor sensitization and conditioned place preference induced by low doses of cocaine.

CONCLUSIONS:

Cocaine induces the rapid induction of Arc and its nuclear accumulation in striatal neurons. Locally, it alters the nucleosomal response, and acts as a brake on chromatin remodeling and gene regulation. These original observations posit Arc as a major homeostatic modulator of molecular and behavioral responses to cocaine. Thus, modulating Arc levels may provide promising therapeutic approaches in drug addiction.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Comportamento Animal / Cocaína / Corpo Estriado / Proteínas do Citoesqueleto / Montagem e Desmontagem da Cromatina / Proteínas do Tecido Nervoso / Neurônios Tipo de estudo: Risk_factors_studies Limite: Animals Idioma: En Ano de publicação: 2017 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Comportamento Animal / Cocaína / Corpo Estriado / Proteínas do Citoesqueleto / Montagem e Desmontagem da Cromatina / Proteínas do Tecido Nervoso / Neurônios Tipo de estudo: Risk_factors_studies Limite: Animals Idioma: En Ano de publicação: 2017 Tipo de documento: Article